This application represents the first competing renewal of our program project, which uses an interdisciplinary team approach to address the unifying hypothesis that most, if not all, aging-related neurodegenerative disorders are caused by the intracellular or extracellular accumulation of specific proteins that have assumed pathogenic conformational states (proteinopathies). The resulting neurodegenerative disorders, which include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD) and other Lewy body diseases (LED), remain largely untreatable and represent a complex biomedical, behavioral and social problem. Medical breakthroughs are urgently needed in this area, and the surest way to such breakthroughs is to determine how exactly these diseases result in the dysfunction and degeneration of nerve cells. Our program addresses this important need by bringing together investigators with diverse areas of expertise, widely overlapping interests in proteinopathies, and an established track record of fruitful collaborative interactions. Our approach takes advantage of a great number of valuable resources and technologies, including robotic microscopy, molecular imaging, genetically engineered mouse models, RNAi mediated gene silencing, and cell type-specific expression of mechanistically informative viral constructs. Using these and other strategies, we will study the processes by which diverse proteins impair neuronal function and survival and compare our results to determine whether there are common mechanisms of neurodegeneration. We will also study the susceptibility of different neuronal populations to common versus disease-specific pathogenic processes to elucidate why these diseases so selectively attack specific neuronal populations. Project 1, "Mechanisms of Cell-Specific Huntingtin-lnduced Neurodegeneration" aims to elucidate cell autonomous and cell non-autonomous mechanisms that contribute to the susceptibility of striatal neurons to mutant huntingtin. Project 2, "Microglial Kynurenine Pathway and Selective Neuronal Vulnerability," will test if genetic or pharmacological inhibition of the microglial kynurenine pathway is protective in mouse models of AD and HD. Project 3, "Apolipoprotein E in Alzheimer's Disease: Cellular Mechanisms," will study the regulation of apolipoprotein E expression in neurons and explore Apin dependent roles of different apolipoprotein E isoforms in the pathogenesis of AD. Project 4, "Causes and Consequences of a-Synuclein Aggregation," will assess in combined models of AD and PD if interactions between a-synuclein and A[unreadable] lead to neurodegeneration of specific neuronal populations through activation of glutamate receptors and proteases that cleave a-synuclein. Project 5, "Mechanisms of Aft-Induced Neuronal Deficits," will test whether the modulation of specific neuronal or glial molecules can block aberrant neuronal overexcitation and ameliorate behavioral abnormalities in mouse models of AD and other proteinopathies. The Cores (A: Administrative, B: Tissue Culture, C: Animal, D: Microscopy/Neuropathology) will provide the common services necessary to accomplish the goals of the program project. Our studies will shed light on diverse neurodegenerative diseases and could provide the knowledge needed to better treat and prevent them.